The discovery that cancer cells actively and passively release their content into the blood stream has opened enormous opportunities for characterizing cancer cells without the need for surgical access to tumor tissue. Instead, a simple draw of blood is sufficient to detect and characterize cancer cells inside a patient’s body. The use of circulating DNA molecules has spurred this field, with circulating RNA molecules (extracellular RNA, exRNA) only recently becoming a seemingly attractive analyte for precision oncology. To advance the exRNA research field and deliver innovations in biomarker research with the ultimate goal of improving cancer patients’ outcomes, I aim to address important open questions on the biology of tumor-derived exRNA in liquid biopsies. More specifically, in animal models and patients, I aim to address how tumor burden impacts tumor exRNA detection sensitivity and how exRNA levels evolve during disease course, treatment, and follow-up, how and to what extent tumor-derived exRNAs are protected from degradation in the blood, and what their half-lives are in circulation. I will apply sequencing-based technologies to profile liquid biopsies from lung cancer xenograft rats and from lung cancer patients. I put forward that the results of my project will be relevant for other cancer types as well.